tbuckley/cabot-search huggingface dataset:
Exploratory biomarker analysis of the phase 3 KEYNOTE-604 study of pembrolizumab plus etoposide for extensive-stage SCLC.
Authors: Charles M. Rudin, Hye Ryun Kim, Alejandro Navarro, Maya Gottfried, Solange Peters, Tibor Csoszi, Parneet Kaur Cheema, Delvys Rodriguez-Abreu, Mira Wollner, James Chih-Hsin Yang, Julien Mazieres, Terufumi Kato, Gregory Peter Kalemkerian, Elisha Dettman, Mackenzie Edmondson, Amir Vajdi, Andrey Loboda, Hazem Edmond El-Osta, Bin Zhao, Mark M. Awad
Journal: Journal of Clinical Oncology (2023)

8503 Background: In the phase 3 KEYNOTE-604 study of extensive-stage small-cell lung cancer (ES-SCLC; NCT03066778), first-line pembrolizumab (pembro) plus etoposide and platinum (EP) significantly improved PFS vs placebo (pbo) plus EP (HR, 0.75; P = 0.0023), with favorable OS (significance threshold not met; HR, 0.80; P = 0.0164). PFS/OS were similar regardless of PD-L1 CPS. In this exploratory analysis, tumor mutational burden (TMB), 18-gene T cell–inflamed gene expression profile (Tcell inf GEP) and SCLC transcriptional subtypes were assessed as correlates of survival. Methods: Patients (pts) eligible for this analysis of KEYNOTE-604 had previously untreated ES-SCLC with evaluable pretreatment tumor samples. TMB was assessed by whole-exome sequencing (WES) of tumor and matched normal DNA. RNA-seq was used to determine Tcell inf GEP and SCLC transcriptional subtypes (ASCL1, POU2F3, NEUROD1, YAP1, or inflamed). Associations of TMB, Tcell inf GEP, and SCLC subtype with OS were analyzed using an adjusted Cox proportional hazards model. 1-sided (pembro + EP) and 2-sided (pbo + EP) P values were calculated for TMB and Tcell inf GEP (prespecified α = 0.05); 2-sided P values were calculated for SCLC subtype (multiplicity-adjusted, α = 0.10). Clinical utility was assessed using prespecified cutoffs of ≥175 mut/exome for TMB and the first tertile for Tcell inf GEP. Clinical data cutoff date was Dec 2, 2019. Results: Of 453 pts randomized in KEYNOTE-604 (ITT), 318 had WES data (pembro + EP, n = 167; pbo + EP, n = 151), and 316 had RNA-seq data (pembro + EP, n = 159; pbo + EP, n = 157). High TMB was positively associated with OS in the pbo + EP group ( P = 0.005) but not the pembro + EP group ( P = 0.450). There was a positive association between higher Tcell inf GEP and OS in the pembro + EP ( P = 0.003) and pbo + EP ( P &lt; 0.005) groups. SCLC subtypes were not associated with OS in either group (pembro + EP, P = 0.960; pbo + EP, P = 0.999). Clinical benefit of pembro + EP over pbo + EP was demonstrated for TMB &lt;175 mut/exome, but not for TMB ≥175 mut/exome. Pembro + EP benefit over pbo + EP was consistent across Tcell inf GEP subgroups. Conclusions: In this exploratory analysis of biomarker subgroups of KEYNOTE-604, TMB and SCLC subtypes were not associated with OS in the pembro + EP group in pts with ES-SCLC. While Tcell inf GEP was positively associated with OS in both treatment groups, no additional OS benefit was observed with pembro + EP. Further research is warranted to better identify predictive biomarkers to immunotherapy. Clinical trial information: NCT03066778 . [Table: see text]
Surgery with adjuvant chemotherapy versus chemoradiation for early-stage large cell neuroendocrine cancer (LCNEC) of the lung: A SEER plus based analysis.
Authors: Anish Shah, Lakshmi Bhavani Potluri, Pravash Budhathoki, Suman Gaire, Dipesh Uprety
Journal: Journal of Clinical Oncology (2023)

e20616 Background: LCNEC of the lung is a rare and highly aggressive tumor with neuroendocrine differentiation. Given its rare occurrence and lack of data from large randomized trials, treatment recommendations are based on the extrapolation of data, primarily from small-cell lung cancer studies. We conducted this study to evaluate the survival difference among patients with LCNEC with an N1 disease between those who received surgery and adjuvant chemotherapy versus definitive chemotherapy and radiotherapy. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER) plus 18 registries database to identify patients diagnosed with LCNEC with tumor stage of T1, T2, or T3 and nodal stage of N1. The study population included patients, 18 years and above, who underwent surgical resection followed by adjuvant chemotherapy and patients who received definitive chemo-radiotherapy for early stage LCNEC. Kaplan-Meier and log rank test were used to compare overall survival (OS) and Cancer specific survival (CSS). Multivariate survival analysis was done using the cox proportional hazards regression model. Results: A total of 178 patients were included, 57.3% (n = 102) were &lt; 65-year-old, 50.56% (n = 90) were male, mostly Caucasian 87.08% (n = 155) and identified as non-Hispanic 93.26% (n = 166). Out of them, 70.22% (n = 125) underwent surgery plus adjuvant chemotherapy and 29.78% (n = 53) underwent chemoradiation. Patients who underwent surgery with adjuvant chemotherapy had higher overall survival (OS) than chemoradiation (37 vs. 11 months respectively). 3-year (49.9% vs. 15.7%) and 5-year OS rates (36.7% vs. 10.4%) were also higher in the earlier group. On multivariate analysis after adjusting for age, gender, race and origin, patients who received chemoradiation had higher hazards as compared to those who received surgery and adjuvant chemotherapy (Hazard ratio: 2.91, 95% Confidence interval (CI):1.93,4.37, P value &lt; 0.001). When examining the cancer specific survival (CSS), similar results were observed with higher CSS in the surgery with adjuvant chemotherapy group (18 vs. 8 months) reaching a statistical significance of P &lt; 0.001 and higher hazards in chemoradiation group (Hazard ratio: 3.33, 95% Confidence interval (CI):2.09,5.28, P value &lt; 0.001). 3-year survival (26.47% vs. 2.7 %) and 5-year CSS rates (11.76% vs. not reached) were also pronounced in the patients treated with surgery with adjuvant chemotherapy. Conclusions: Our study demonstrates that patients with early stage LCNEC (T1-3 N1) disease treated with surgery and adjuvant chemotherapy had statistically significant overall and cancer specific survival rates compared to those treated with chemoradiation.
FDG-PET/CT response and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.
Authors: Milton Jose De Barros E Silva, Monique Celeste Tavares, Joao Paulo S. N. Lima, Antonio C. Buzaid, Daniel Garcia, Veridiana Pires De Camargo, Andre Molina, Eduardo Bertolli, Matheus Lobo, Alexander Christopher Jonathan Van Akkooi, Clovis Pinto, Rafaela Brito De Paula, Eduardo Lima, José Augusto Rinck, Joao Duprat
Journal: Journal of Clinical Oncology (2023)

9585 Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1 mg/kg (N3+I1) for two cycles for clinical stage III melanoma have shown rates of major pathological response (MPR) of approximately 60%.The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-responders have a worse outcome and early identification of this group may allow us to tailor the treatment before surgery. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant N3+I1 for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2023, 28 patients with clinical stage III melanoma treated with N3+I1 who had baseline and preoperative 18F-FDG PET were identified. Gender: 20 (71%) males, median age (range):55 (34-78), BRAFV600E/K mut: 15(53%), positive nodes on baseline PET/CT:1 = 26 (92%), 2 = 1(4%), and 3 = 1(4%). All known lesions identified by CT scan were also captured by FGD-PET/CT. Site of node(s): axilla = 12 (43%), cervical = 10 (36%), and inguinal = 6(21%). All but one patient received 2 cycles of N3+IP1(1 patient had grade 3 toxicity and received only one cycle). Pathological response: MPR = 19(68%), non-MPR: 8 (28%), and 1(4%) did not undergo surgery due to widespread progression. An increase in maximum SUV and/or appearance of new lesion(s), n = 8(28%), was correlated to non-MPR or metastatic disease in all cases, including a patient who developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of inflammatory mediastinal lymph-nodes. The median increase was (range): +73% (+11% to 483%). Reduction or stable maximum SUV with no appearance of new lesion, n = 20 (72%), was associated with MPR in 19 patients (95%). One patient,who had G3 colitis (with the need of infliximab), had 32% of reduction in maximum SUV but 100% of viable tumor cells on pathological report. The median decrease (range) was -76% (-1.2% to -100%). Conclusions: FGD-PET/CT may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.
Real-world analysis of ICI efficacy in ES-SCLC patients with and without brain metastases: A call for inclusion in clinical trials.
Authors: Yuanzhen Cao, Muhammad Zubair Afzal, Ziyao Lu, Aditya Sharma, Jonathan P. Pirruccello, Keisuke Shirai
Journal: Journal of Clinical Oncology (2023)

e20621 Background: Immune checkpoint inhibitors (ICIs) have proven successful in treating extensive stage small-cell lung cancer (ES-SCLC). Atezolizumab, a PD-L1 inhibitor, is approved as first-line therapy for ES-SCLC in combination with chemotherapy. SCLC has a high incidence to spread to the brain with more than 50% of patients developing brain metastases (BM) during their clinical course. However, patients with BM have frequently been excluded from clinical trials due to their perceived poor prognosis. This study aimed to assess the efficacy of ICI in achieving disease response and managing intracranial disease in patients with ES-SCLC. Methods: We conducted a retrospective study on patients with biopsy-confirmed ES-SCLC treated with at least one cycle of atezolizumab/carboplatin/etoposide combination from 2015 to 2022. Overall survival (OS), progression-free survival (PFS) and radiographic response were noted in patients with and without BM. Intracranial (IC) response was documented in patients with radiographic evidence of BM who had at least one follow-up brain imaging after the start of ICI. Results: A total of 83 patients were included, 39.3% (n = 33) of which had BM. Median follow-up was 8 (95%CI: 4.5-11.6) months. Baseline characteristics were summarized in the table below. Disease progression occurred in 90.9% patients with BM and death in 51.5%. Among 21 patients who fulfilled IC response assessment criteria, one (4.8%) had complete response, four (19.0%) had partial response, two (9.5%) had stable disease and fourteen (66.7%) had disease progression. Median duration of IC response was 5.3 (95%CI: 0.00-20.35) months; IC objective response rate was 23.8%. No difference was found in OS (10 vs. 30 months, P = 0.3) or PFS (6 vs. 7 months, P = 0.18) in patients with and without BM respectively. Patients with &gt; 3 BM (n = 16) had inferior OS (7 vs. 21 months, P = 0.01) and PFS (5 vs. 6 months, P = 0.002) compared to those with ≤3 BM. Conclusions: This study demonstrated that ICI achieved similar outcomes in patients with and without BM and produced meaningful intracranial response in patients with BM. Therefore, further clinical trials on ES-SCLC should encompass patients with BM, especially those with ≤3 BM. Future research on a larger, more diverse patient population is warranted. [Table: see text]
The association of the comorbidity polypharmacy score (CPS) with functional limitations, frailty, and mortality in older adults with gastrointestinal malignancies.
Authors: Brian Westbrook, Smith Giri, Christian Harmon, Jing Jin, Mustafa Al-Obaidi, Grant Richard Williams, Darryl Alan Outlaw
Journal: Journal of Clinical Oncology (2023)

12036 Background: Older adults share a growing burden of cancer morbidity and mortality. The presence of comorbid medical conditions and polypharmacy may present significant challenges to cancer management for older adults. Although geriatric assessment (GA) is recommended to personalize treatment for older adults with cancer, it remains underutilized in routine oncology practice, and how best to measure comorbidity and polypharmacy remain unknown. The Comorbidity Polypharmacy Score (CPS), which is the sum of the number of comorbid medical conditions and medications for a patient, has been validated in other medical fields. Here we review the association of CPS with key outcomes among older adults with gastrointestinal (GI) malignancy. Methods: The Cancer and Aging Resilience Evaluation (CARE) tool is a brief, patient-completed GA developed for older adults with cancer at the University of Alabama at Birmingham (UAB). For patients enrolled in the CARE registry, diagnosed with a new GI malignancy between September 2017 and April 2021, we calculated a CPS based upon the number of patient-reported medical comorbid conditions and daily medications. Patients were separated into two groups, those with CPS ≥ 15, or high-risk, and those with CPS &lt; 15. Multivariable analyses were adjusted for age, sex, race, cancer type, and cancer stage, and were performed to examine the potential association between high-risk CPS and falls, functional limitations, frailty, and mortality. Results: 548 patients were included in this study with a mean age of 69.7 years; 44.9% female and 23.9% Black. Common GI malignancies included colorectal (30.8%), pancreatic (25.5%), hepatobiliary (17.7%), and gastroesophageal (10.8%). Patients with CPS ≥ 15 were more likely to report falls (adjusted odds ratio [aOR] 3.39, 95% CI 1.91-6.02), dependence in activities of daily living (ADL) (aOR 3.07, 95% CI 1.67-5.66) and instrumental ADL (aOR 3.81, 95% CI 2.02-7.20), and have frailty (aOR 5.17, 95% CI 2.84-9.39). There was not a statistically significant association with either six-month or twelve-month survival. Conclusions: CPS was associated with falls, functional limitations, and frailty, but not survival, among older adults with GI malignancies. This association highlights the potential role of CPS as an efficient screening tool for older adults with cancer who would benefit from more comprehensive comorbidity and medication review.
Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES).
Authors: Janine Joseph, Li Tang, Jens Hillengass, Ola Landgren, Saad Zafar Usmani, Alexander M. Lesokhin, Kirsten B. Moysich, Urvi A Shah
Journal: Journal of Clinical Oncology (2023)

e20062 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder (PCD) with a prevalence of 3% in adults over age 50. The annual risk of progression to multiple myeloma (MM) is 1%. Although one cohort study in Caucasians reported that diets low in certain plant-based foods were associated with MGUS (Thordardottir et al. 2018), research on diet and MGUS in a more diverse population is scarce. Given that diet can vary greatly across ethnic/racial groups, we conducted a population-based study with multiple races and ethnicities. Methods: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study in 373 individuals with MGUS and 1,406 controls frequency matched on age, body mass index, NHANES cycle, sex, and race. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. MGUS status was determined by blood screening. Unconditional multivariable logistic regressions were used to model associations between MGUS and intake, with odds ratios and 95% confidence intervals reported for the highest quantile of intake. Results: Daily intake of several food and beverage groups were significantly associated with MGUS, low-risk MGUS (LRMGUS) or intermediate/high-risk MGUS (IHRMGUS). Whole-grain bread, oats, and rice; fruits and vegetables; tomatoes; and cruciferous vegetables were associated with significantly lower risk (28-78%). Sugar- and artificially sweetened beverages were associated with significantly higher risk (34-113%). Interestingly, there were more significant findings for LRMGUS than IHRMGUS, suggesting potential contributing etiologic differences for LRMGUS and IHRMGUS. Conclusions: Our study shows that low intake of whole grains, fruits and vegetables and high intake of sweetened beverages are associated with MGUS. The identification of dietary risk factors for MGUS in a diverse population is of direct public health relevance. These findings also provide rationale for exploration of mechanistic links between diet and PCDs, such as the ongoing studies NCT04920084, NCT05640843, and NCT05312255. [Table: see text]
Site of metastasis (SoM) and its impact on clinical outcomes in 8 cancer cohorts.
Authors: Rohini George, Neeraj Singh, Laura Vidal, Ewa Hajek, Dorota Skalska, Kamal S. Saini, Smita Agrawal
Journal: Journal of Clinical Oncology (2023)

6590 Background: The prognosis of metastatic cancer is in general poor. This can be affected by several factors including age, histology, treatment choices &amp; SoM etc. Methods: This retrospective study leverages ConcertAI’s deeply curated Patient360 datasets for 8 solid cancers to assess the impact of SoM on the outcomes of patients. For the purpose of this analysis, we focused on the most common SoM (bone, brain, lung &amp; liver). Patients had either a Single SoM (SSM) or Multiple SoM (MSM) and we focused this analysis on patients with SSM. The overall survival (OS) &amp; progression free survival (PFS) from the date of metastasis as well as the time to metastasis (TTM) from initial diagnosis were determined for each cohort. We also computed a consolidated OS &amp; PFS for all patients with MSM. Results: 140K patients were included in this study of which 60K patients had a SoM. The distribution of SoM is dependent on the primary cancer type. For example, in breast &amp; prostate cancer, bone metastasis accounts for 50-80 % of the metastatic cohort whereas it is only 8-21% in lung &amp; melanoma. As expected, the overall values of OS/PFS were primarily governed by the primary cancer type (Table), but this analysis provides further interesting insights: 1. Within a cohort, there were significant differences in the prognosis of patients based on the SoM . Brain &amp; liver had a poorer prognosis compared to the other SoM across most cohorts. 2. The relative prognosis for some SoM were dependant on the primary cancer type. For example, there was a very significant difference between the OS/PFS values in the breast cancer cohort when comparing brain vs bone as SoM. However, in the lung cancer cohort, this difference was less pronounced, and the trend was flipped. 3. For some cohorts the SSM for certain sites had a worse prognosis than the MSM. In breast cancer the OS of the brain &amp; liver SoM was worse than the MSM. 4. The TTM is also dependent on the primary cancer and there is a correlation between the average TTM and the OS of the cohort. Conclusions: The patterns of cancer metastasis and the absolute and relative prognosis for a particular SoM is dependent on the primary cancer type. Such insights from a large real-world data study can impact clinical decisions regarding the aggressiveness of treatment based on the primary cancer type as well as the metastatic site. [Table: see text]
Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.
Authors: Luis G. Paz-Ares, Astrid Paulus, Marius Zemaitis, Saulius Cicenas, Zanete Zvirbule, Enriqueta Felip, Annika Sanfridson, Camilla Rydberg-Millrud, Susanne Magnusson, Nedjad Losic, Ignacio Garcia-Ribas
Journal: Journal of Clinical Oncology (2023)

9089 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1 st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3 rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1 st or 2 nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2 nd line post pembrolizumab) showed complete responses, one observed after &gt;40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3 rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]